Increasing evidence shows that smoking-obtained nicotine is indicated to improve cognition and mitigate certain symptoms of schizophrenia. In this study, we investigated whether chronic nicotine treatment alleviated MK-801-induced schizophrenia-like symptoms and cognitive impairment in mice. Mice were injected with MK-801 (0.2 mg/kg, i.p.), and the behavioral deficits were assessed using prepulse inhibition (PPI) and T-maze tests. We showed that MK-801 caused cognitive impairment accompanied by increased expression of PDZ and LIM domain 5 (Pdlim5), an adaptor protein that is critically associated with schizophrenia, in the prefrontal cortex (PFC). Pretreatment with nicotine (0.2 mg · kg⁻¹ · d⁻¹, s.c., for 2 weeks) significantly ameliorated MK-801-induced schizophrenia-like symptoms and cognitive impairment by reversing the increased Pdlim5 expression levels in the PFC. In addition, pretreatment with nicotine prevented the MK-801-induced decrease in CREB-regulated transcription coactivator 1 (CRTC1), a coactivator of CREB that plays an important role in cognition. Furthermore, MK-801 neither induced schizophrenia-like behaviors nor decreased CRTC1 levels in the PFC of Pdlim5^−/− mice. Overexpression of Pdlim5 in the PFC through intra-PFC infusion of an adreno-associated virus AAV-Pdlim5 induced significant schizophrenia-like symptoms and cognitive impairment. In conclusion, chronic nicotine treatment alleviates schizophrenia-induced memory deficits in mice by regulating Pdlim5 and CRTC1 expression in the PFC.

越来越多的证据表明，通过吸烟获得的尼古丁可以改善认知并减轻精神分裂症的某些症状。在这项研究中，我们研究了长期尼古丁治疗是否可以减轻 MK-801 诱导的小鼠精神分裂症样症状和认知障碍。给小鼠注射 MK-801（0.2 mg/kg，腹腔注射），并使用前脉冲抑制 (PPI) 和 T 迷宫测试评估行为缺陷。我们发现，MK-801 会导致认知障碍，并伴有前额皮质 (PFC) 中 PDZ 和 LIM 结构域 5 (Pdlim5) 的表达增加，Pdlim5 是一种与精神分裂症密切相关的接头蛋白。尼古丁预处理（0.2 mg·kg ^-1 · d ^-1 ，皮下注射，持续 2 周）通过逆转 PFC 中增加的 Pdlim5 表达水平，显着改善了 MK-801 诱导的精神分裂症样症状和认知障碍。此外，尼古丁预处理可防止 MK-801 诱导的 CREB ​​调节转录共激活因子 1 (CRTC1) 减少，CRTC1 是 CREB ​​的共激活因子，在认知中发挥重要作用。此外，MK-801 既不会诱导 Pdlim5 ^−/−小鼠的精神分裂症样行为，也不会降低 PFC 中的 CRTC1 水平。通过在 PFC 内输注肾上腺相关病毒 AAV-Pdlim5，Pdlim5 在 PFC 中过度表达，诱导显着的精神分裂症样症状和认知障碍。总之，长期尼古丁治疗通过调节 PFC 中 Pdlim5 和 CRTC1 的表达来减轻精神分裂症引起的小鼠记忆缺陷。